Pharmacological considerations for tenofovir and emtricitabine
to prevent HIV infection
Peter L. Anderson
*, Jennifer J. Kiser
, Edward M. Gardner
, Joseph E. Rower
, Amie Meditz
and Robert M . Grant
Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO, USA;
Division of Infectious Diseases, University of
Colorado Denver, Aurora, CO, USA;
Denver Public Health, Denver, CO, USA;
Gladstone Institute of Virology and Immunology, University
of California San Francisco, CA, USA
*Corresponding author. E-mail: firstname.lastname@example.org
The use of antiretroviral medications in HIV-negative individuals as pre-exposure prophylaxis (PrEP) is a prom-
ising approach to prevent HIV infection. Tenofovir disoproxil fumarate (TDF) and emtricitabine exhibit desirable
properties for PrEP including: favourable pharmacokinetics that support infrequent dosing; few major drug-drug
or drug-food interactions; an excellent clinical safety record; and pre-clinical evidence for efﬁcacy. Several large,
randomized, controlled clinical trials are evaluating the safety and efﬁcacy of TDF and emtricitabine for this new
indication. A thorough understanding of variability in drug response will help determine future investigations in
the ﬁeld and/or implementation into clinical care. Because tenofovir and emtricitabine are nucleos(t)ide ana-
logues, the HIV prevention and toxicity effects depend on the triphosphate analogue formed intracellularly.
This review identiﬁes important cellular pharmacology considerations for tenofovir and emtricitabine, which
include drug penetration into relevant tissues and cell types, race/ethnicity/pharmacogenetics, gender, cellular
activation state and appropriate episodic or alternative dosing strategies based on pharmacokinetic principles.
The current state of knowledge in these areas is summarized and the future utility of intracellular pharmaco-
kinetics/pharmacodynamics for the PrEP ﬁeld is discussed.
Keywords: clinical pharmacology, intracellular pharmacology, pharmacokinetics, pharmacodynamics, pharmacogenomics,
nucleoside analogue pharmacology
Although HIV prevention strategies such as promotion of safe sex
practices and clean needle exchange programmes are effective,
additional approaches are needed to help reduce the number of
new HIV infections, which are estimated at 2.7 million cases
The ideal prevention tool would be a protective
vaccine, but the feasibility and timelines for a highly effective
HIV vaccine remain unclear.
A new hope for a powerful HIV prevention tool has emerged
in chemoprophylaxis with antiretroviral medications, referred
to as pre-exposure prophylaxis (PrEP).
4 – 6
PrEP is the use of
antiretroviral medications in HIV-negative persons to prevent
HIV infection should HIV exposure take place. Antiretroviral
drugs are currently used for HIV prevention in other settings,
including after high-risk HIV exposures such as needlesticks
[post-exposure prophylaxis (PEP)], rape or high-risk sexual
exposures [non-occupational PEP (nPEP)] or for prevention of
mother to child transmission (PMTCT).
7 – 9
One of the differences between the prevention uses listed
above and PrEP is that the target population for PrEP may not
have the same imminent risk of HIV exposure and may be
young adults in prime health.
For these reasons, PrEP will
require a very low toxicity proﬁle along with proven beneﬁt for
an acceptable risk–beneﬁt balance. Until recently there were
few antiretroviral agents that provided an adequate safety or tol-
erability proﬁle for an acceptable risk–beneﬁt ratio. This situation
is changing, however, as newer agents with more favourable
safety proﬁles become available.
In addition to excellent safety and tolerability, prototypical
PrEP agents should exhibit high cost-effectiveness, a relatively
benign HIV resistance proﬁle should PrEP fail and pharmacokinetic
properties that support once-daily or less frequent dosing. Ideally
the pharmacokinetics should be resilient to drug interactions
and food effects, and should be effective and safe during
periods of missed doses (‘pharmacokinetically forgiving’).
Drug distribution into tissues and cells susceptible to HIV infection
would be another important requirement.
Tenofovir and emtricitabine, two nucleos(t)ide analogue
reverse transcriptase inhibitors (NRTIs), have emerged as viable
PrEP agents based upon the favourable pharmacological charac-
teristics described above, considerable safety experience in
humans and compelling pre-clinical data. A number of large, ran-
domized, controlled trials in humans are under way or have been
completed to evaluate the safety and efﬁcacy of tenofovir
or tenofovir disoproxil fumarate (TDF) with and without
# The Author 2010. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
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J Antimicrob Chemother 2011; 66: 240–250
doi:10.1093/jac/dkq447 Advance Access publication 30 November 2010